Type 2 diabetes is a medical condition that affects the endocrine and metabolic systems. It is defined by high levels of glucose in the blood, a condition known as hyperglycemia. This is produced by a disruption in the metabolism of sugar, protein, fat, water, and electrolytes, which occurs due to either insufficient production of insulin or reduced sensitivity of target cells to insulin [7]. The illness has several causes and its development is intricate. The prevalence of this illness is rising with the growing number of Chinese people, and it is increasingly affecting younger individuals. The medical profession asserts that there is a strong correlation between obesity, inflammation, gut flora, and type 2 diabetes. If relevant epidemiological research demonstrate that obesity is the primary and enduring factor contributing to type 2 diabetes [8]. Several investigations have shown that the accumulation of abdominal fat in individuals with acquired obesity is the primary cause of reduced insulin sensitivity [9].
Research has shown a favorable correlation between insulin resistance and the elevation of inflammatory markers in relation to inflammation [10]. Intestinal flora refers to the microorganisms that live in the human gut. These microorganisms may be categorized as symbiotic bacteria, opportunistic bacteria, and harmful bacteria. Research has shown that an imbalance in the microorganisms present in the intestines may cause chronic inflammation in the intestinal environment, either directly or indirectly. This inflammation can disrupt the internal environment and ultimately result in the development of insulin resistance [11]. Berberine hydrochloride is an alkaloid derived from isoquinoline. Studies have shown that berberine hydrochloride may enhance insulin sensitivity and decrease blood glucose levels in individuals by addressing factors such as obesity, inflammation, and intestinal flora [12]. This research synthesized the aforementioned findings to elucidate the impact of berberine hydrochloride on inflammation and intestinal microbiota in rats with type 2 diabetes.
Regarding the weight of rats, this research demonstrated a consistent increase in weight across all four groups over the 0-4 week period of the trial. Throughout the duration of the trial, the body weight consistently grew. However, there was a notable difference in body weight between the group treated with berberine hydrochloride and the modeling group, particularly at week 1. Both groups had lower body weights compared to the normal control group and metformin. During the 0, 2, 3, and 4-week period, the body weight of the rats with type 2 diabetes followed the following order: normal control group > metformin group > berberine hydrochloride group > model group. This suggests that the weight increase of the rats with type 2 diabetes was lower compared to the normal rats. By administering metformin and berberine hydrochloride, it is hypothesized that berberine hydrochloride may ameliorate the lipid metabolic dysfunction in rats with type 2 diabetes. In a meta-analysis, Zhao et al. [13] shown that berberine has favorable effectiveness and safety when used for treating dyslipidemia. Yao et al. [14] shown that berberine has the ability to safeguard skeletal muscle against excessive lipid buildup by enhancing the production of new mitochondria and enhancing the oxidation of fatty acids. This process is reliant on the activation of AMPK/PGC-1α. The aforementioned findings align with the outcomes of this investigation, all of which substantiate the beneficial impact of berberine hydrochloride on the dysregulation of lipid metabolism in individuals with diabetes mellitus.
Prior pharmacological research has shown that berberine hydrochloride has the ability to decrease blood TC and TG levels, while simultaneously increasing HDL-C levels. This is achieved by the inhibition of cholesterol production, reduction of liver lipid content, and facilitation of lipid transformation and excretion in liver tissues [15]. Research has verified that berberine hydrochloride can enhance the levels of serum apolipoprotein A1 and decrease the levels of apolipoprotein B. This, in turn, facilitates the transportation of cholesterol to lower blood fat levels. Additionally, it inhibits the formation of very low density lipoprotein cholesterol on smooth muscle cell membranes, thereby reducing the formation of foam cells and minimizing damage to the vascular endothelium. Consequently, this study observed a change in the weight of the middle mouse [16].
Furthermore, there were no notable disparities seen in fasting blood glucose (FBG), fasting insulin (FINS), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels across the four groups prior to the experimental modeling. Following the modeling process, the levels of FNG, FINS, IL-6, and TNF-α were considerably elevated in the modeling group, berberine hydrochloride group, and metformin group. These levels were notably higher compared to the normal control group. Following the intervention, the levels of FBG, FINS, IL-6, and TNF-α were dramatically reduced in both the berberine hydrochloride group and the metformin group, compared to before the modeling. Conversely, in the modeling group, the levels of FBG, FINS, IL-6, and TNF-α were significantly elevated. There was no notable disparity between the berberine hydrochloride group and the metformin group, however, both groups exhibited considerably lower values compared to the modeling group. These findings demonstrate the successful establishment of a diabetic rat model in this work, and reveal that berberine hydrochloride effectively improves blood glucose and insulin levels while reducing inflammatory mediators. Furthermore, the observed effects are comparable to those of metformin.
Liang et al. [17] shown that the impact of berberine on blood glucose levels became negligible due to the prolonged duration of therapy exceeding 90 days, the administration of a daily dosage over 2g, and the inclusion of patients aged over 60 years old. The efficacy of the combination of berberine and hypoglycemic medicines surpasses that of berberine alone or hypoglycemic drugs individually. The impact of berberine may vary depending on the amount and length of therapy, as well as the age of the patient. Pei et al. [18] shown that BBR suppressed the increase in bovine LDL-induced galactose agglutinin-3 and macrophage activation. Galactose agglutinin-3 overexpression hinders the suppressive impact of BBR on macrophage activation. BBR stimulates the activation of phosphoric acid -AMPK and hinders the movement of phosphoric acid -NF-κB P65 into the nucleus. The inhibitory impact of BBR on galactose agglutinin-3 production and macrophage activation was removed by inhibiting AMPK and activating NF-κB. The aforementioned findings were in line with the outcomes of our investigation, which validated the inhibitory effect of berberine hydrochloride on the advancement of type 2 diabetes in rats and its ability to decrease the levels of inflammatory mediators in the bloodstream. The precise explanation may be that insulin resistance in type 2 diabetes is intricately linked to the quantity of inflammatory substances, among which il-6 has been shown to stimulate hyperinsulinism in the first phase of diabetes. When insulin production reaches a particular threshold, it may cause damage to insulin β cells, either indirectly or directly. This damage can be caused by factors such as encouraging B cell development and increasing favorable fatty acids. As a result, patients may develop insulin resistance [19]. Research has shown that TNF-α may affect peripheral target tissues via endocrine mechanisms, resulting in insulin resistance. Alternatively, it might indirectly cause insulin resistance by promoting tyrosine phosphorylation of IRS-1 [20]. Wu et al. [21] shown that BBR has the ability to modulate the activity of several cellular components including cAMP, PKA, PPM1B, PPAR γ LRP1, GLUT4, NF-κB P65, JNK, pIKK β Ser181, IKK β, IRS-1 Ser307, and IRS-1. The expression of Irs-2 Ser731, IRS-2, PI3K P85, and AKT Ser473 plays a role in regulating the development of diabetes. These signaling molecules had a strong correlation with IL-6 and TNF-α in the individuals under investigation. By regulating signaling pathways such as NF-KB, JNK, and IKKβ, the amount of inflammatory mediators in the serum of patients may be reduced. This, in turn, leads to a decrease in blood glucose and blood insulin levels in rats, ultimately relieving insulin resistance in type 2 diabetes.
Regarding the organization of intestinal flora, this research found no notable disparity in the quantity of Lactobacillus and enterostreptococcus among the four groups of rats prior to the modeling process. In the modeling group, berberine hydrochloride group, and metformin group, the quantity of lactobacillus reduced while the number of enterostreptococcus rose after modeling. Following intervention, the berberine hydrochloride group and metformin group exhibited a considerable increase in the quantity of lactobacillus compared to the pre-modeling stage. The abundance of Streptococcus intestinalis was significantly reduced in the berberine hydrochloride group, followed by the metformin group, normal control group, and model group. Conversely, the number of lactobacillus was highest in the berberine hydrochloride group, followed by the metformin group, normal control group, and model group. The findings suggest that berberine hydrochloride has the ability to enhance the composition of the intestinal microflora in rats with type 2 diabetes, hence contributing to the management of diabetes. The impact of this treatment on enhancing the structure of intestinal microbiota was superior to that of metformin. Zhang et al. [22] shown that both berberine and metformin decreased food consumption, body mass, blood glucose, and HbA1c levels in mice. Both interventions successfully decreased the concentration of short-chain fatty acids (SCFAs) in the intestines, lowered the amount of lipopolysaccharide (LPS) in the bloodstream, mitigated intestinal inflammation, and restored the integrity of the intestinal barrier. The administration of either metformin or berberine caused changes in the gut microbiome of DB/DB mice, resulting in an increase in the abundance of bacteria that produce short-chain fatty acids (such as butyrate bacteria, coccidiomycetes, and ruminococcus) and a decrease in harmful bacteria. Furthermore, there was a notable rise in the prevalence of other beneficial bacteria, such as Lactobacillus. Additionally, the administration of berberine and metformin influenced the makeup of the gut microbiome, resulting in a decrease in body weight, blood glucose levels, and inflammation in the intestines of DB/DB mice. This exemplifies their efficacy in mitigating diabetic complications in this setting.
Wang et al. [23] shown that berberine has the potential to decelerate the advancement of prediabetic adipose rats to T2DM by enhancing the production of GLP-2, increasing intestinal permeability, and enhancing the structure of intestinal microbiota. The aforementioned findings were in line with the outcomes of this investigation, which verified that the utilization of berberine hydrochloride may regulate the composition of intestinal microflora and enhance the state of diabetes in rats with diabetes. The three explanations are: short-chain fatty acids, bile acids, and endotoxins. Research has shown that gut microbiota may alleviate the body's impaired capacity to break down carbs and convert them into short-chain fatty acids. An imbalance in the intestinal flora may result in aberrant quantities and structures of short-chain fatty acids. This imbalance can cause chronic inflammation in the gut, enhance insulin resistance via several mechanisms, and trigger death of islet β cells. Furthermore, the presence of diabetes also results in the disruption of gut flora, creating a harmful cycle due to the influence of interaction [24]. Furthermore, there are research indicating a correlation between it and the metabolic processes of bile acids inside the human body. In the endotoxin hypothesis, the survival of gram-negative endotoxin in the intestinal tract is mostly driven by the presence of illness, and individuals with diabetes commonly have co-occurring obesity. Furthermore, several studies have verified a strong correlation between lipid metabolism disorder in individuals with diabetes and the elevation of endotoxin levels. Prolonged elevation of endotoxin levels leads to metabolic endotoxemia, which subsequently triggers chronic inflammation, insulin resistance, and the progression of the disease. The efficacy of berberine hydrochloride in inhibiting lipid metabolism disorder and reducing inflammatory mediators has been shown in the aforementioned findings. Consequently, the elimination of intestinal endotoxin may enhance the composition of the gut flora and mitigate insulin resistance. Hence, this might perhaps explain why berberine hydrochloride outperforms metformin in enhancing the composition of gut microbiota [25].
The study has high level of novelty and high significant as this is the only study in which subsequently, Realtime PCR technology was used to ascertain the presence of Lactobacillus and Enterococcus. The total sample size has been highest till now which is 60 and no study till date has used the proper grouping with control group.
In conclusion both berberine hydrochloride and metformin have the ability to enhance the advancement of disease in type 2 diabetic rats. However, berberine hydrochloride surpasses metformin in its effectiveness in ameliorating the levels of inflammatory mediators, diminishing insulin resistance, and enhancing the structure of the intestinal microflora in rats.